Fungicidal 5-dialkylamino-4-nitrosulfonamidothiophenes

ABSTRACT

Novel thiophenes of the formula ##STR1## wherein R 1  is alkyl; R 2  is alkyl; one X is hydrogen, fluoro, chloro or bromo and the other X is --SC 2  N(R 3 )(R 4 ) wherein R 3  is alkyl or aryl and R 4  is hydrogen or haloalkylthio, are useful for the prevention or cure of fungal infections.

DESCRIPTION OF THE PRIOR ART

French Pat. No. 1,563,736, issued Apr. 18, 1969, to Pillon et al,discloses pesticidal 2-sulfonamido-3,4,5-trichlorothiophenes. A. Buzaset al, "Ann. Pharm. France" 19, 499 (1961) [C.A. 56, 6603c (1962) ]discloses diruretic 2-sulfonamidothiophenes.

DESCRIPTION OF THE INVENTION

The thiophenes of the invention are represented by the formula (I)##STR2## wherein R¹ is alkyl of 1 to 6 carbon atoms; R² is alkyl of 1 to6 carbon atoms; one X is fluoro, chloro or bromo and the other X is--SC₂ N(R³) (R⁴) wherein R³ is alkyl of 1 to 6 carbon atoms or phenylsubstituted with up to 2 (0 to 2) of the same or different substituentsselected from trifluoromethyl, trichloromethyl, fluoro, chloro, bromo,nitro, or alkyl of 1 to 3 carbon atoms and R⁴ is H or haloalkylthio of 1to 3 carbon atoms and 1 to 7 of the same or different halogens of atomicnumber 9 to 35 (fluoro, chloro or bromo).

Representative alkyl R¹, R² and R³ groups are methyl, ethyl, propyl,isopropyl, butyl and hexyl. Representative substituted phenyl R³ groupsare o-trifluoromethylphenyl, m-trifluoromethylphenyl,p-trichloromethylphenyl, o-fluorophenyl, m-chlorophenyl, p-bromophenyl,2,4-dichlorophenyl, 3,5-dibromophenyl, 3-bromo-4-chlorophenyl, o-tolyl,2,4-dimethylphenyl, p-nitrophenyl and 2-cloro-4-methylphenyl.Representative haloalkylthio R⁴ groups are chloromethylthio,trifluoromethylthio, dichloromethylthio, trichloromethylthio,fluorodichloromethylthio, tribromoethylthio, 2,2,2-trichloroethylthio,1,2,2,2-tetrachloroethylthio, 1,1,2,2-tetrabromoethylthio,pentachloroethylthio, 2,2,3,3,3-pentabromopropylthio and3,3,3-trichloropropylthio.

The preferred R¹ and R² groups are alkyl of 1 to 3 carbon atoms,especially methyl. One X group preferably is hydrogen, cloro or bromo,and the other X group preferably is SO₂ N(R³)(R⁴) wherein R³ is loweralkyl of 1 to 3 carbon atoms or phenyl substituted with up to 2trifluoromethyl, fluoro, chloro or bromo and R⁴ is hydrogen orpolyhaloalkylthio of 1 to 2 carbon atoms and 2 to 5 of the same ordifferent halogens selected from chloro or bromo. When X is hydrogen, itis preferably substituted at the 3 position of the thiophene ring. WhenX is fluoro, chloro or bromo, it is preferably substituted at the 2position of the thiophene ring.

A preferred class of thiophenes of the formula (I) is that wherein one Xis hydrogen, chloro or bromo, and the other X is --SO₂ N(R³) (R⁴)wherein R³ is alkyl of 1 to 3 carbon atoms or phenyl substituted with upto 2 trifluoromethyl, trichloromethyl, fluoro, chloro, bromo or alkyl of1 to 3 carbon atoms and R⁴ is hydrogen.

Another preferred class of thiophenes of formula (I) is that wherein oneX is hydrogen, chloro or bromo and the other X is --SO₂ N(R³) (R⁴)wherein R³ is alkyl of 1 to 3 carbon atoms or phenyl substituted with upto 2 of the same or different substituents selected fromtrifluoromethyl, trichloromethyl, fluoro, chloro, bromo or alkyl of 1 to3 carbon atoms and R⁴ is polyhaloalkylthio of 1 to 2 carbon atoms and 2to 5 of the same or different halogens selected from chloro or bromo.

The thiophenes of the invention wherein R⁴ is hydrogen are prepared byreacting a 5-halo-4-nitrosulfonamidothiophene (II) with a dialkylaminecompound (III). The thiophenes of the invention wherein R² ishaloalkylthio are prepared by sulfenylating the resultingsulfonamidothiophene (IV) with a haloalkylsulfenyl halide (V) in thepresence of an acid acceptor. These reactions are depicted in reactions(1) and (2) for a 2-sulfonamidothiophene or 3-sulfonamidothiophene (II).##STR3## wherein R¹, R² and R³ have the same significance as previouslydefined, SR⁵ is a haloalkylthio R⁴ group as previously defined, and Y ischloro or bromo.

Reaction (1) is conducted by reacting the sulfonamidothiophene (II) andthe amine (III) in an inert diluent at a temperature of 0° to 100° C.Preferably a molar excess of the amine or aniline (III), or an acidacceptor as defined below, is used as an acid acceptor for the hydrogenhalide produced in the reaction. Reaction (2) is conducted by reactingsubstantially equimolar quantities of the5-dialkylamino-4-nitrosulfonamidothiophene (IV) and the sulfenylchloride (V) in the presence of an acid acceptor. Suitable acidacceptors are organic amines such as pyridine compounds, e.g., pyridineor alpha-picoline, and lower trialkylamines, e.g., triethylamine ortripropylamine. Generally, at least one mol of acid acceptor is employedfor each mol of sulfenyl chloride. The reaction is normally conducted inan inert liquid diluent, e.g., organic solvents such as chlorinatedhydrocarbons. The product (I) is isolated and purified by conventionalprocedures such as extraction, filtration, crystallization andchromatography.

The sulfonamidothiophenes of formula (II) are suitably prepared byreacting a 5-halo-4-nitrothienylsulfonyl chloride with an alkylamine(NHR³) by conventional procedures. The 4-nitro-substitutedthienylsulfonyl chloride reactants are suitably prepared by nitrating athienylsulfonyl chloride with nitric acid in a suitable solvent such asconcentrated sulfuric acid or acetic anhydride.

The compounds of the invention are useful for controlling fungi,particularly plant fungal infections caused by Botrytis cinerea, leafblights caused by organisms such as Septoria apii, Alternaria solaniconidia and Phytophthora infestans conidia, powdery mildew caused byorganisms such as Erysiphe polygoni and E. chicoraciarum, and otherfungal infections caused by organisms such as Pythrium ultimum,Helminthosporum sativum, Fusarium moniliforme, Rhizoctonia solani,Monolinia fructicola and Uromyces phaseoli typica. However, somefungicidal compounds of the invention may be more fungicidally activethan others against particular fungi.

When used as fungicides, the compounds of the invention are applied infungicidally effective amounts to fungi and/or their habitats, such asvegatative hosts and non-vegetative hosts, e.g., animal products. Theamount used will, of course, depend on several factors such as the host,the type of fungus and the particular compound of the invention. As withmost pesticidal compounds, the fungicides of the invention are notusually applied full strength, but are generally incorporated withconventional, biologically inert extenders or carriers normally employedfor facilitating dispersion of active fungicidal compounds, recognizingthat the formulation and mode of application may affect the activity ofthe fungicide. Thus, the fungicides of the invention may be formulatedand applied as granules, as powdery dusts, as wettable powders, asemulsifiable concentrates, as solutions, or as any of several otherknown types of formulations, depending on the desired mode ofapplication.

Wettable powders are in the form of finely divided particles whichdisperse readily in water or other dispersant. These compositionsnormally contain from about 5-80% fungicide, and the rest inertmaterial, which includes dispersing agents, emulsifying agents, andwetting agents. The powder may be applied to the soil as a dry dust, orpreferably as a suspension in water. Typical carriers include fuller'searth, kaolin clays, silicas, and other highly absorbent, readilywettable, inorganic diluents. Typical wetting, dispersing or emulsifyingagents include, for example: the aryl and alkylaryl sulfonates and theirsodium salts; alkylamide sulfonates, including fatty methyl taurides;alkylaryl polyether alcohols, sulfated higher alcohols, and polyvinylalcohols; polyethylene oxides, sulfonated animal and vegetable oils;sulfonated petroleum oils, fatty acid esters of polyhydric alcohols andthe ethylene oxide addition products of such esters; and the additionproducts of long-chain mercaptans and ethylene oxide. Many other typesof useful surface-active agents are available in commerce. Thesurface-active agent, when used, normally comprises from 1% to 15% byweight of the fungicidal composition.

Dusts are freely flowing admixtures of the active fungicide with finelydivided solids such as talc, natural clays, kieselguhr, pyrophyllite,chalk, diatomaceous earths, calcium phosphates, calcium and magnesiumcarbonates, sulfur, lime, flours, and other organic and inorganic solidswhich act as dispersants and carriers for the toxicant. These finelydivided solids have an average particle size of less than about 50microns. A typical dust formulation useful herein contains 75% silicaand 25% of the toxicant.

Useful liquid concentrates include the emulsifiable concentrates, whichare homogeneous liquid or paste compositions which are readily dispersedin water or other dispersant, and may consist entirely of the fungicidewith a liquid or solid emulsifying agent, or may also contain a liquidcarrier, such as xylene, heavy aromatic naphthas, isophorone, and othernonvolatile organic solvents. For application, these concentrates aredispersed in water or other liquid carrier, and are normally applied asa spray to the area to be treated.

Other useful formulations for fungicidal applications include simplesolutions of the active fungicide in a dispersant in which it iscompletely soluble at the desired concentration, such as acetone,alkylated naphthalenes, xylene, or other organic solvents. Granularformulations, wherein the fungicide is carried on relatively coarseparticles, are of particular utility for aerial distribution or forpenetration of cover-crop canopy. Pressurized sprays, typically aerosolswherein the active ingredient is dispersed in finely divided form as aresult of vaporization of a low-boiling dispersant solvent carrier, suchas the Freons, may also be used. All of these these techniques forformulating and applying fungicides are well known in the art.

The percentages by weight of the fungicide may vary according to themanner in which the composition is to be applied and the particular typeof formulation, but in general comprise 0.5 to 95% of the toxicant byweight of the fungicidal composition.

The fungicidal compositions may be formulated and applied with otheractive ingredients, including other fungicides, insecticides,nematocides, bactericides, plant growth regulators, fertilizers, etc.

EXAMPLES EXAMPLE 1 Preparation of5-dimethylamino-4-nitro-2-(N-methyl-N-1,1,2,2-tetrachloroethylthiosulfonamido)thiophene

An 80-g (0.68 mol) sample of 2-chlorothiophene was added dropwise to acooled (dry ice/acetone bath, about -10° to -15° C.) and stirredsolution of 160 g (1.38 mol) of chlorosulfonic acid. After the additionwas completed, the reaction mixture was stirred at 50° C for 2 hours,cooled, and then poured into 250 g of ice. The aqueous reaction mixturewas extracted with methylene chloride. The methylene chloride extractwas washed with saturated aqueous sodium bicarbonate solution, washedwith water, dried over magnesium sulfate, and evaporated to give 40 g of5-chloro-2-thienylsulfonyl chloride.

A 32.5-g (0.15 mol) sample of 5-chloro-2-thienylsulfonyl chloride wasadded in small portions to a stirred solution of 150 ml concentratednitric acid and 150 ml concentrated sulfuric acid. After the additionwas completed, the reaction mixture was stirred at about 25° Covernight. The reaction mixture was then diluted with ice water andfiltered to give the 5-chloro-4-nitro-2-thienylsulfonyl chlorideproduct.

A mixture of 20.2 g (0.2 mol) triethylamine and 26.2 g of a 40% aqueousmethylamine solution (0.2 mol methylamine) was added dropwise to acooled and stirred solution of 53.7 g (0.2 mol)5-chloro-4-nitro-2-thienylsulfonyl chloride in 200 ml acetone. Aftercompletion of the addition, the reaction mixture was allowed to warm to25° C and stirred for 2 hours. The acetone was removed by evaporation.The reaction mixture was then diluted with methylene chloride, washedwith water, dried over magnesium sulfate, and evaporated to give the5-chloro-4-nitro-2-(N-methylsulfonamido)thiophene product.

A 20.2-g (0.2 mcl) sample of triethylamine was added dropwise to acooled (0° C) solution of 25.7 g (0.1 mol)5-chloro-4-nitro-2-(N-methylsulfonamido)thiophene and 8.2 g (0.1 mol)dimethylamine hydrochloride in 200 ml methanol. The reaction mixture wasthen allowed to warm to about 25° C and heated at reflux for 2 hours.The reaction mixture was then evaporated to dryness under reducedpressure, diluted with methylene chloride, washed with water, dried overmagnesium sulfate and evaporated to give an oil. The oil wascrystallized from benzene to give5-dimethylamino-4-nitro-2-(N-methylsulfonamido)thiophene, as dark greencrystals.

A 6.6 g (0.0283 mol) sample of 1,1,2,2-tetrachloroethylsulfenyl chloridewas added dropwise to a cooled (0° C.) solution of 7.5 g (0.0283 mol)5-dimethylamino-4-nitro-2-(N-methylsulfonamido)thiophene in 150 mlmethylene chloride. The reaction mixture was stirred at about 25° C forseveral hours, washed with water, dried over magnesium sulfate andevaporated to give the product as an oil which crystallized from hexaneas a solid, m.p. 122°-124° C.

EXAMPLE 2 Preparation of5-dimethylamino-4-nitro-2-chloro-3-(N-methyl-N-trichloromethylthiosulfonamido)thiophene

A 96.8-g (0.632 mol) sample of 2,5-dichlorothiophene was added dropwiseto a cooled (dry ice/acetone bath, about -10° to -15° C.) and stirredsolution of 163 g (1.39 mol) of chlorosulfonic acid. After the additionwas completed, the reaction mixture was stirred at 50° C for 2 hours,cooled, and then poured into 200 g of ice. The aqueous reaction mixturewas extracted with methylene chloride. The methylene chloride extractwas washed with saturated aqueous sodium bicarbonate solution, washedwith water, dried over magnesium sulfate, and evaporated to give 87 g of2,5-dichloro-3-thienylsulfonyl chloride.

A 55.8-g (0.22 mol) sample of 2,5-dichloro-3-thienylsulfonyl chloridewas added in small portions to a stirred solution of 150 ml concentratednitric acid and 150 ml concentrated sulfuric acid. After the additionwas completed, the reaction mixture was stirred at about 25° Covernight. The reaction mixture was then diluted with ice water andfiltered to give the crude 2,5-dichloro-4-nitro-3-thienylsulfonylchloride product. The product was washed with water and dried.Recrystallization from methylene chloride gave the product as a brownsolid, m.p. 89°-91° C.

A 30.4-g (0.33 mol) sample of aniline was added dropwise to a solutionof 49.1 g (0.165 mol) 2,5-dichloro-4-nitro-3-thienylsulfonyl chloride in250 ml methylene chloride cooled in a dry-ice/acetone bath (-50° C). Thereaction mixture was then allowed to warm about 25° C and stirred atabout 25° C overnight. The reaction mixture was filtered to remove theaniline hydrochloride salt. The filtrate was washed with water, driedover magnesium sulfate and evaporated to give 41 g2,5-dichloro-4-nitro-3-(N-phenylsulfonamido)thiophene, m.p. 127°-129° C.

A 12.2-g (0.122 mol) sample of triethylamine was added dropwise to asolution of 4.9 g (0.61 mol) dimethylamine hydrochloride and 21.5 g(0.61 mol), 2,5-dichloro-4-nitro-3-(N-phenylsulfonamido)thiophene in 200ml methanol. The reaction mixture was heated under reflux for 3 hours.The methanol was then removed under reduced pressure and the residue wasextracted with methylene chloride. The methylene chloride extract waswashed with water, dried over magnesium sulfate and evaporated to givethe crude5-dimethylamino-4-nitro-2-chloro-3-(N-phenylsulfonamido)thiopheneproduct. Crystallization from hexane gives the pure product as a brownsolid, m.p. 143°-144° C.

A 2.3 g (0.023 mol) sample of triethylamine was added dropwise to asolution of 7 g (0.0194 mol)5-dimethylamino-4-nitro-2-chloro-3-(N-phenylsulfonylamido)thiophene and3.6 g (0.0194 mol) trichloromethylsulfenyl chloride in 200 ml methylenechloride at -10° C. The reaction mixture was allowed to warm to about25° C. and then heated under reflux for 1 hour. The reaction mixture wascooled, washed with water, dried over magnesium sulfate and stripped togive the5-dimethylamino-4-nitro-2-chloro-3-(N-phenyl-N-trichloromethylthiosulfonamido)thiopheneproduct as a brown solid, m.p. 140°-141° C.

Other compounds of the invention were prepared by procedures similar tothat of Examples 1-2. These compounds and the compounds of Examples 1-2are tabulated in Table I.

EXAMPLE 3 Botrytis Cinerea Control

5-dimethyl-4-nitro-2-chloro-3-(N-methyl-N-trichloromethylthiosulfonamido)thiophenewas tested for Botrytis cinerea control using detached, well-developedprimary leaves of a 4-6 week old horsebean plant. The leaves were dippedinto a 40-ppm solution of the test compound in acetone and watercontaining a small amount of a nonionic emulsifier, then taken out andplaced in a petri plate lined with two pieces of filter paper. Theleaves were allowed to dry while the fiber paper was kept moist byadding water as required. The treated leaves were then inoculated withthe spores of Botrytis cinerea fungus grown on potato dextrose agarplates. The plates were covered after inoculation and kept at 23.5° C.The filter-paper linings of the plates were kept saturated with waterthroughout the test. The rate of disease incidence was determined in 3to 5 days, when the disease symptoms were fully evident on nontreatedcheck leaves. The percent disease control provided by the test compoundwas calculated as the percentage disease reduction based on thenon-treated check leaves.

5-dimethylamino-4-nitro-2-chloro-3-(N-methyl-N-trichloromethylthiosulfonamido)thiophenewas found to give 47% control.

EXAMPLE 4 Tomato Late Blight

Representative compounds of the invention were tested for the control ofthe Tomato Late Blight organism Phytophthora infestans conidia.Five-to-six-week-old tomato (variety Bonny Best) seedlings were used.The tomato plants were sprayed with a 250-ppm solution of the testcompound in acetone, water, and a small amount of a non-ionicemulsifier. The sprayed plants were then inoculated one day later withthe organisms, placed in an environmental chamber and incubated at66°-68° F and 100% relative humidity for at least 16 hours. Followingthe incubation, the plants were allowed to dry and then were maintainedat 60-80% relative humidity for approximately 7 days. The percentdisease control provided by a given test compound was based on thepercent disease reduction relative to untreated check plants.

By the above procedure,5-dimethylamino-4-nitro-2-(N-methyl-N-trichloromethylthiosulfonamido)thiophene gave 84% control and5-dimethylamino-4-nitro-2-(N-methyl-N-1,1,2,2,-tetrachloroethylthiosulfonamido)thiophenegave 64% control.

EXAMPLE 5 Tomato Early Blight

Representative compounds of the invention were tested for the control ofthe Tomato Early Blight organism, Alternaria solani conidia. Tomato(variety Bonny Best) seedlings of 6 to 7 weeks old were used. The tomatoplants were sprayed with a 250-ppm solution of the test compound in anacetone-and-water solution containing a small amount of a non-ionicemulsifier. The sprayed plants were inoculated one day later with theorganism, dried and maintained at 60-80% relative humidity for about 12days. Percent disease control was based on the percent diseasedevelopment on untreated check plants.

By the above procedure,5-dimethylamino-4-nitro-2-(N-methyl-N-1,1,2,2-tetrachloroethylthiosulfonamido)thiophenegave 68% control and5-dimethyl-4-nitro-2-chloro-3-(N-phenyl-N-trichloromethylthiosulfonamido)thiophenegave 77% control.

EXAMPLE 6 Celery Late Blight

Representative compounds of the invention were tested for the control ofCelery Late Blight using celery (Utah) plants 11 weeks old. The CeleryLate Blight organism was Septoria apii. The celery plants were sprayedwith solutions of the candidate toxicant mixed with acetone, water and anonionic emulsifier. The plants were then inoculated with the organismand placed in an environmental chamber and incubated at 66°-68° F in100% relative humidity for an extended period of time (approximately 48hours). Following the incubation, the plants were allowed to dry andthen were maintained at a 60-80% relative humidity for approximately 14days. The percent disease control provided by a given candidate toxicantis based on the percent disease reduction relative to untreated checkplants.

By the above procedure,5-dimethyl-4-nitro-2-(N-methyl-N-trichloroethylthiosulfonamido)thiophenegave 75% control,5-dimethyl-4-nitro-2-(N-methyl-N-1,1,2,2-tetrachloroethylthiosulfonamido(thiophene)gave 91% control and5-dimethyl-4-nitro-2-chloro-3-(N-methyl-N-1,1,2,2-tetrachloroethylthiosulfonamido)thiophenegave 68% control.

                                      TABLE I                                     __________________________________________________________________________    Compounds of the formula:                                                      ##STR4##                                                                     Com-                                       Elemental Analysis                 pound                              Melting Sulfur    Chlorine                 No.  X.sup.1        X.sup.2        Point, ° C                                                                     Calc.                                                                              Found                                                                              Calc.                                                                              Found               __________________________________________________________________________    1    H              SO.sub.2 N(CH.sub.3) (SCCl.sub.2 CCl.sub.2 H)                                                122-124 20.8 20.7 30.6 28.6                2    H              SO.sub.2 N(CH.sub.3) (SCCl.sub.3)                                                            131-132 23.2 22.6 25.7 24.2                3    H              SO.sub.2 N(iC.sub.3 H.sub.7) (SCCl.sub.3)                                                    115-116 21.7 20.8 24.0 23.7                4    H              SO.sub.2 N(iC.sub.3 H.sub.7) (SCCl.sub.2 CCl.sub.2                                           127-128 19.6 19.4 28.9 27.6                6    H              SO.sub.2 Nφ (SCCl.sub.3)                                                                 167-169 18.3 17.9 20.3 19.9                7    H              SO.sub.2 N(CH.sub.3) (SCCl.sub.3)                                                            129-130 21.4 21.4 31.6 32.4                8    SO.sub.2 N(CH.sub.3) (SCCl.sub.2 CCl.sub.2 H)                                                Cl             104-107 19.3 19.8 35.6 32.9                9    SO.sub.2 Nφ (SCCl.sub.3)                                                                 Cl             140-141 18.8 17.1 27.7 26.3                10   H              SO.sub.2 NH(iC.sub.3 H.sub.7)                                                                117-119 21.9 21.9 --   --                  11   SO.sub.2 NH(CH.sub.3)                                                                        Cl             143-144 21.4 21.2 11.8 12.4                12   SO.sub.2 NHφ                                                                             Cl             143-144 17.6 18.6 --   --                  __________________________________________________________________________     φ = phenyl                                                           

What is claimed is:
 1. A compound of the formula ##STR5## wherein R¹ isalkyl of 1 to 6 carbon atoms; R² is alkyl of 1 to 6 carbon atoms; one Xis hydrogen, fluoro, chloro or bromo and the other X is --SO₂ N(R³) (R⁴)wherein R³ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or phenylsubstituted with 1 to 2 of the same or different substituents selectedfrom trifluoromethyl, trichloromethyl, fluoro, chloro, bromo, nitro oralkyl of 1 to 3 carbon atoms and R⁴ is haloalkylthio of 1 to 3 carbonatoms and 1 to 7 of the same or different halogens selected from fluoro,chloro or bromo.
 2. The compound of claim 1 wherein R⁴ ispolyhaloalkylthio of 1 to 2 carbon atoms and 2 to 5 of the same ordifferent halogens selected from chloro or bromo.
 3. The compound ofclaim 2 wherein R⁴ is trichloromethylthio or tetrachloroethylthio. 4.The compound of claim 2 wherein R³ is alkyl of 1 to 6 carbon atoms. 5.The compound of claim 2 wherein the X group at the 3 position of thethiophene ring is hydrogen. 6.5-dimethylamino-4-nitro-2-(N-methyl-N-1,1,2,2-tetrachloroethylthiosulfonamido)thiophene,according to claim
 5. 7. The compound of claim 2 wherein the X group atthe 2 position of thiophene ring is chloro or bromo. 8.5-dimethylamino-4-nitro-2-chloro-3-(N-phenyl-N-trichloromethylthiosulfonamido)thiophene,according to claim
 7. 9.5-dimethylamino-4-nitro-2-(N-methyl-N-trichloroethylthiosulfonamido)thiophene,according to claim 5.